Program Director/Principal Investigator (Last, First, Middle): ABSTRACT Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) share common modes of transmission. As a result, people with HIV (PWH) are disproportionately affected by chronic HBV. Globally, an estimated 2.7 million PWH have HBV coinfection. In high endemic areas such as Africa, up to 25% of PWH also have HBV coinfection. In the United States, 5 to 10% of PWH have HBV coinfection. Persons with HBV/HIV coinfection have a higher risk for liver cirrhosis, hepatocellular carcinoma (HCC) and liver related death compared to those without HIV. The risk of life-threatening complications due to HBV is strongly related to the level of viral replication. Thus, the goal of treatment is to achieve sustained virologic suppression. In HBV/HIV co-infected patients, tenofovir (TFV) disoproxil fumarate (TDF) or TFV alafenamide (TAF) plus emtricitabine (FTC) or lamivudine (3TC) is recommended as essential components of antiretroviral therapy (ART). Tenofovir is the most potent nucleotide analogue for HBV treatment. While TFV resistance leading to suboptimal therapy is extremely rare up to 8 years of use, incomplete suppression of HBV replication on TDF-based therapy is common. The reason(s) why some HBV/HIV co-infected individuals fail to achieve undetectable HBV viremia despite full suppression of HIV on TDF-based ART is also unknown. We propose that higher levels of ART adherence and/or drug exposure at the site of viral replication is needed for HBV suppression than for HIV. The efficacy of TFV is dependent on intracellular concentrations of the active phosphate anabolite, TFV diphosphate (TFVdp). We hypothesize that insufficient intracellular TFVdp concentrations will be the central mechanism associated with HBV non-suppression, and covariates of intracellular TFVdp pharmacokinetics (PK) would predict risk of unsuppressed HBV. The primary goal of this project is to determine the contribution of TFVdp PK and/or medication adherence to suboptimal HBV suppression on TDF-based ART. We will accomplish our goal through the following specific aims: 1.) Determine the relationship between TFVdp concentrations in DBS and PBMCs and HBV suppression in HIV/HBV co-infected patients on TDF-containing ART; 2.) Determine demographic and genetic covariates of intracellular TFVdp concentration and HBV virologic suppression in HIV/HBV co-infected patients on TDF-containing ART. Defining the covariates of TFV PK and virologic response (PK/PD) for HBV could inform individualized strategies to optimize HBV treatment response. Discoveries from this project could form the basis for developing and testing adherence-based or genotype-guided interventions to optimize HBV outcomes in HIV co-infected patients. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page